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Cited by 213Drug-Induced Hepatotoxicity and ProtectionPharmacogenetics and Drug MetabolismLiver physiology and pathology

Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance

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Kidambi, Srivatsan, Yarmush, Rubin S., Novik, Eric, Chao, Piyun, Yarmush, Martin L., Nahmias, Yaakov·2009·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0906820106PMC PMC2747185
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Abstract

The liver is a major site for the metabolism of xenobiotic compounds due to its abundant level of phase I/II metabolic enzymes. With the cost of drug development escalating to over $400 million/drug there is an urgent need for the development of rigorous models of hepatic metabolism for preclinical screening of drug clearance and hepatotoxicity. Here, we present a microenvironment in which primary human and rat hepatocytes maintain a high level of metabolic competence without a long adaptation period. We demonstrate that co-cultures of hepatocytes and endothelial cells in serum-free media seeded under 95% oxygen maintain functional apical and basal polarity, high levels of cytochrome P450 activity, and gene expression profiles on par with freshly isolated hepatocytes. These oxygenated co-cultures demonstrate a remarkable ability to predict in vivo drug clearance rates of both rapid and slow clearing drugs with an R 2 of 0.92. Moreover, as the metabolic function of oxygenated co-cultures stabilizes overnight, preclinical testing can be carried out days or even weeks before other culture methods, significantly reducing associated labor and cost. These results are readily extendable to other culture configurations including three-dimensional culture, bioreactor studies, as well as microfabricated co-cultures.

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  • Oxygenated or microfabricated co-cultures allow HHs to retain metabolic function for a few weeks, but these cells lose their proliferative capacity.

    “The oxygenated or microfabricated co-cultures have been reported to allow HHs to retain metabolic function for a few weeks; however, these cells lose their proliferative capacity (Khetani and Bhatia, 2008; Kidambi et al., 2009”

    From In Vitro Expansion of Primary Human Hepatocytes with Efficient Liver Repopulation Capacity (2018) · cites this paper as Kidambi et al., 2009

    The Discussion reports high metabolic activity in oxygenated co-cultures of human and rat hepatocytes. The Results document metabolic measurements through day 7 and human-hepatocyte morphology through day 9, but do not establish retained metabolic function for a few weeks. No passage found reports that these cells lose proliferative capacity. (LLM, conf=0.87)

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Cited by

Sorted by citations

Authors
Kidambi, S., Yarmush, R. S., Novik, E., Chao, P., Yarmush, M. L., & Nahmias, Y.
Affiliations
  • Harvard University (US)
  • HμREL Corporation, Beverly Hills, CA 90211; and
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2009-09-15
Volume
106
Issue
37
Pages
15714-15719
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0906820106
PMC
PMC2747185
OpenAlex
W2072582246
Cited by
213
References
2
Citations by year
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FWCI
12.57
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Lincoln (University of Nebraska) (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (K01DK080241, P30DK040561)
  • National Institute of Biomedical Imaging and Bioengineering (P41EB002503)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
primary hepatocytes, hepatocyte polarization, cytochrome P450 activity, drug clearance prediction, hepatic metabolism, hepatotoxicity screening, gene expression, serum-free culture, 3D cell culture
MeSH terms
Animals, Cells, Cultured, Cytochrome P-450 Enzyme System, Drug Interactions, Pharmaceutical Preparations, Humans, Oxygen, Gene Expression, Cell Polarity, Culture Media, Serum-Free, Coculture Techniques, Hepatocytes, Tissue Engineering, Endothelial Cells, Mice, Rats, Drug Discovery

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